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Background: Hepatocellular carcinoma (HCC) surveillance is underutilized, with Methods: We conducted a retrospective cohort study of individuals with cirrhosis using claims data from Medicare, Medicaid, and private insurance plans in North Carolina. We included individuals ≥ 18 years with a first occurrence of an ICD-9/10 code for cirrhosis between January 1, 2010, and June 30, 2018. The outcome was HCC surveillance by abdominal ultrasound, CT, or MRI. We estimated 1- and 2-year cumulative incidences for HCC surveillance and assessed longitudinal adherence to surveillance by computing the proportion of time covered (PTC). Results: Among 46,052 individuals, 71% were enrolled through Medicare, 15% through Medicaid, and 14% through private insurance. The overall 1-year cumulative incidence of HCC surveillance was 49% and the 2-year cumulative incidence was 55%. For those with an initial screen in the first 6 months of their cirrhosis diagnosis, the median 2-year PTC was 67% (Q1, 38%; Q3, 100%). Conclusions: HCC surveillance initiation after cirrhosis diagnosis remains low, though it has improved slightly over time, particularly among individuals with Medicaid. Impact: This study provides insight into recent trends in HCC surveillance and highlights areas to target for future interventions, particularly among patients with nonviral etiologies.

Supplementary Table 8 includes one-year cumulative incidences for HCC surveillance overall and by insurance type, by calendar year of cirrhosis diagnosis (% and 95% confidence intervals).

Supplementary Table 12 includes the one-year cumulative incidences for HCC surveillance overall and by insurance type, by calendar year of cirrhosis diagnosis, excluding individuals with decompensated cirrhosis (% and 95% confidence intervals).

Supplementary Table 7 includes baseline characteristics of individuals with cirrhosis eligible for HCC surveillance – Medicare only (N, %) (N=32,723).

The Supplementary Methods includes detailed descriptions for calculating the Proportion of Time Covered measures.

Supplementary Table 5 includes baseline characteristics of individuals with cirrhosis eligible for HCC surveillance – private insurance only (N, %) (N=6,530).

Supplementary Table 9 includes two-year cumulative incidences for HCC surveillance overall and by insurance type, by calendar year of cirrhosis diagnosis (% and 95% confidence intervals).

Supplementary Table 6 includes baseline characteristics of individuals with cirrhosis eligible for HCC surveillance – Medicaid insurance only (N, %) (N=6,790).

Background:Hepatocellular carcinoma (HCC) surveillance is underutilized, with Methods:We conducted a retrospective cohort study of individuals with cirrhosis using claims data from Medicare, Medicaid, and private insurance plans in North Carolina. We included individuals ≥ 18 years with a first occurrence of an ICD-9/10 code for cirrhosis between January 1, 2010, and June 30, 2018. The outcome was HCC surveillance by abdominal ultrasound, CT, or MRI. We estimated 1- and 2-year cumulative incidences for HCC surveillance and assessed longitudinal adherence to surveillance by computing the proportion of time covered (PTC).Results:Among 46,052 individuals, 71% were enrolled through Medicare, 15% through Medicaid, and 14% through private insurance. The overall 1-year cumulative incidence of HCC surveillance was 49% and the 2-year cumulative incidence was 55%. For those with an initial screen in the first 6 months of their cirrhosis diagnosis, the median 2-year PTC was 67% (Q1, 38%; Q3, 100%).Conclusions:HCC surveillance initiation after cirrhosis diagnosis remains low, though it has improved slightly over time, particularly among individuals with Medicaid.Impact:This study provides insight into recent trends in HCC surveillance and highlights areas to target for future interventions, particularly among patients with nonviral etiologies.

Supplementary Table 4 includes descriptive statistics of the cohort, by cirrhosis etiology and by insurance type.

Supplementary Table 3 includes hypothetical examples for calculating the Proportion of Time Covered measures.

This letter to the editor expresses concerns related to immortal time bias that may partially account for recently published study results.

Regorafenib is a tyrosine kinase inhibitor approved by the FDA for the treatment of patients with chemotherapy refractory metastatic colorectal cancer (mCRC). Regorafenib inhibits signaling through multiple receptors associated with angiogenesis, metastasis, and tumor immunity. Here, we report biomarker results from LCCC1029, a randomized, placebo-controlled, phase II trial of chemotherapy ± regorafenib in patients with second-line mCRC. A panel of 20 soluble protein biomarkers (termed the Angiome) was assessed in the plasma of 149 patients from the LCCC1029 trial both at baseline and along the treatment continuum. Baseline protein levels were analyzed for prognostic and predictive value for progression-free survival (PFS) and overall survival (OS). Changes in protein levels during treatment were analyzed for potential pharmacodynamic effects. Six markers (HGF, IL6, PlGF, VEGF-R1, OPN, and IL6R) were found to be prognostic for PFS. Nine markers (IL6, TIMP-1, PlGF, VCAM-1, ICAM-1, OPN, TSP-2, HGF, and VEGF-R1) were prognostic for OS. Higher baseline levels of OPN (Pintx = 0.0167), VCAM-1 (Pintx = 0.0216), and PDGF-AA (Pintx = 0.0435) appeared to predict for PFS benefit from regorafenib compared with placebo. VCAM-1 was also potentially predictive of OS benefit from regorafenib compared with placebo (Pintx = 0.0124). On-treatment changes of six markers reflected potential on-target effect of regorafenib. Consistent results were observed in an Italian cohort where 105 patients with late-stage mCRC received regorafenib monotherapy. The key findings of this study suggest that VCAM-1 may be a predictive biomarker for regorafenib benefit, while multiple protein markers may be prognostic of outcome in patients with mCRC.

Figure S1, consort diagram. Table S1, pts characteristics. Table S2, baseline levels. Table S3, prognostic markers. Table S4, adjusted prognostic markers. Table S5, early changes. Table S6, late changes at disease progression.

Emergency department visits and hospitalizations are common among people receiving cancer treatment, accounting for a large proportion of spending in oncology care and negatively affecting quality of life. As oncology care shifts toward value- and quality-based payment models, there is a need to develop interventions that can prevent these costly and low-value events among people receiving cancer treatment. Risk stratification programs have the potential to address this need and optimally would consist of three components: (1) a risk stratification algorithm that accurately identifies patients with modifiable risk(s), (2) intervention(s) that successfully reduce this risk, and (3) the ability to implement the risk algorithm and intervention(s) in an adaptable and sustainable way. Predictive modeling is a common method of risk stratification, and although a number of predictive models have been developed for use in oncology care, they have rarely been tested alongside corresponding interventions or developed with implementation in clinical practice as an explicit consideration. In this article, we review the available published predictive models for treatment-related toxicity or acute care events among people receiving cancer treatment and highlight challenges faced when attempting to use these models in practice. To move the field of risk-stratified oncology care forward, we argue that it is critical to evaluate predictive models alongside targeted interventions that address modifiable risks and to demonstrate that these two key components can be implemented within clinical practice to avoid unplanned acute care events among people receiving cancer treatment.

Background The comparative effectiveness of trimodality therapy vs definitive chemoradiation for treating locally advanced esophageal cancer in older adults is uncertain. Existing trials lack generalizability to older adults, a population with heightened frailty. We sought to emulate a hypothetical trial comparing these treatments using real-world data. Methods A cohort of adults aged 66-79 years diagnosed with locally advanced esophageal cancer between 2004 and 2017 was identified in the Surveillance Epidemiology and End Results–Medicare database. The clone-censor-weight method was leveraged to eliminate time-related biases when comparing outcomes between treatments. Outcomes included overall mortality, esophageal cancer–specific mortality, functional adverse events, and healthy days at home. Results A total of 1240 individuals with adenocarcinomas and 661 with squamous cell carcinomas were identified. For adenocarcinomas, the standardized 5-year risk of mortality was 73.4% for trimodality therapy and 83.8% for definitive chemoradiation (relative risk [RR] = 0.88, 95% confidence interval [CI] = 0.82 to 0.95). Trimodality therapy was associated with mortality risk reduction for squamous cell carcinomas (RR = 0.87, 95% CI = 0.70 to 1.01). The 1-year incidence of functional adverse events was higher in the trimodality group (adenocarcinomas RR = 1.40, 95% CI = 1.22 to 1.65; squamous cell carcinomas RR = 1.21, 95% CI = 1.00 to 1.49). Over 5 years, trimodality therapy was associated with 160 (95% CI = 67 to 229) and 177 (95% CI = 51 to 313) additional home days in individuals with adenocarcinomas and squamous cell carcinomas, respectively. Conclusions Compared with definitive chemoradiation, trimodality therapy was associated with reduced mortality but increased risk of function-related adverse events. Discussing these tradeoffs may help optimize care plans.

Background Cetuximab is often administered to patients with KRAS wild-type (KRAS-WT) metastatic colorectal cancer (mCRC), although resistance inevitably develops. We hypothesized that co-inhibition of the epidermal growth factor receptor (EGFR) with cetuximab and downstream cyclin-dependent kinases (CDK) 4/6 with palbociclib would be effective for anti-EGFR rechallenge in KRAS-WT mCRC. Methods We designed a single-arm, Simon’s 2-stage, phase II trial of cetuximab and palbociclib in KRAS-WT mCRC treated with ≥2 prior lines of therapy. We report here on cohort B rechallenging patients with anti-EGFR-based therapy who had disease control of at least 4 months on prior anti-EGFR therapy. Primary endpoint was disease control rate (DCR) at 4 months. Results Ten evaluable patients were enrolled in this cohort. The 4-month DCR was 20%, which did not fulfill the prespecified 4-month DCR rate to continue. Median progression-free survival was 1.8 months and median overall survival was 6.6 months. Three patients had stable disease, although overall response rate was 0%. Most common treatment-related grades 3-4 adverse events were lymphopenia and leukopenia. Conclusion Selection of patients for anti-EGFR rechallenge using clinical criteria alone was insufficient to identify response to palbociclib + cetuximab. Additional biomarkers are needed to select anti-EGFR rechallenge and circulating tumor DNA (ctDNA) analysis is planned for samples collected in this study. (ClinicalTrials.gov Identifier: NCT03446157)

Background: Early treatment of hepatocellular carcinoma (HCC) is associated with improved survival, but many patients with HCC do not receive therapy. We aimed to examine factors associated with HCC treatment and survival among incident patients with HCC in a statewide cancer registry. Materials and Methods: All patients with HCC from 2003 through 2013 were identified in the North Carolina cancer registry. These patients were linked to insurance claims from Medicare, Medicaid, and large private insurers in North Carolina. Associations between prespecified covariates and more advanced HCC stage at diagnosis (ie, multifocal cancer), care at a liver transplant center, and provision of HCC treatment were examined using multivariate logistic regression. A Cox proportional hazards model was developed to assess the association between these factors and survival. Results: Of 1,809 patients with HCC, 53% were seen at a transplant center Conclusions: In this population-based cohort of patients with HCC, Medicare/Medicaid insurance, rural residence, and Black race were associated with lower provision of HCC treatment and poorer survival. Efforts should be made to improve access to care for these vulnerable populations.

Regorafenib is a tyrosine kinase inhibitor approved by the FDA for the treatment of patients with chemotherapy refractory metastatic colorectal cancer (mCRC). Regorafenib inhibits signaling through multiple receptors associated with angiogenesis, metastasis, and tumor immunity. Here, we report biomarker results from LCCC1029, a randomized, placebo-controlled, phase II trial of chemotherapy ± regorafenib in patients with second-line mCRC. A panel of 20 soluble protein biomarkers (termed the Angiome) was assessed in the plasma of 149 patients from the LCCC1029 trial both at baseline and along the treatment continuum. Baseline protein levels were analyzed for prognostic and predictive value for progression-free survival (PFS) and overall survival (OS). Changes in protein levels during treatment were analyzed for potential pharmacodynamic effects. Six markers (HGF, IL6, PlGF, VEGF-R1, OPN, and IL6R) were found to be prognostic for PFS. Nine markers (IL6, TIMP-1, PlGF, VCAM-1, ICAM-1, OPN, TSP-2, HGF, and VEGF-R1) were prognostic for OS. Higher baseline levels of OPN (Pintx = 0.0167), VCAM-1 (Pintx = 0.0216), and PDGF-AA (Pintx = 0.0435) appeared to predict for PFS benefit from regorafenib compared with placebo. VCAM-1 was also potentially predictive of OS benefit from regorafenib compared with placebo (Pintx = 0.0124). On-treatment changes of six markers reflected potential on-target effect of regorafenib. Consistent results were observed in an Italian cohort where 105 patients with late-stage mCRC received regorafenib monotherapy. The key findings of this study suggest that VCAM-1 may be a predictive biomarker for regorafenib benefit, while multiple protein markers may be prognostic of outcome in patients with mCRC.

For over a decade, sorafenib remained the only systemic agent with proven clinical efficacy for patients with advanced hepatocellular carcinoma (HCC). Recent years have seen a proliferation of agents. In the first line, lenvatinib was found to be non-inferior to sorafenib in terms of overall survival (OS), with significantly better progression-free survival and objective response rate. Meanwhile, encouraging efficacy signals were observed in phase I/II studies of immune checkpoint inhibitors as monotherapy in HCC. Although subsequent phase III trials failed to demonstrate statistically significant benefit in OS, other clinically meaningful outcomes were observed, including long-term disease control with a favorable toxicity profile. In addition, a synergistic response has been postulated based on the interplay between antiangiogenic molecular targeted agents and immunotherapy. On this basis, interest has turned toward combination strategies of immunotherapy with these standard-of-care medications in the hope of improving treatment efficacy for advanced HCC, while maintaining tolerable safety profiles. Indeed, preliminary results from phase I studies of lenvatinib plus pembrolizumab and atezolizumab plus bevacizumab have proved favorable, prompting phase III investigations in the frontline setting, and for atezolizumab plus bevacizumab, these positive findings have been substantiated by recent reporting of phase III data from IMbrave150. In this review, we will present the currently available data on combination therapy atezolizumab plus bevacizumab in advanced HCC, and compare these findings to other promising combination treatments, most notably that of lenvatinib plus pembrolizumab.

PURPOSE: Although studies in other clinical areas have shown that patient-clinician communication can positively influence adherence to medications, little is known about how oncologists address medication counseling during routine office visits. We describe patient-oncologist office-based discussions of oral chemotherapy treatment. METHODS: Transcripts of 24 patient-oncologist office visits were obtained from a national database. Patients were aged ≥ 19 years and prescribed capecitabine for colorectal cancer. We developed a structured coding worksheet using medication-counseling concepts previously identified as important to medication adherence and a grounded approach. Two coders reviewed transcripts for oncologists’ provision of medication information, assessment of patients’ adherence to medication, and the provision of self-management support for management of adverse effects. We assessed interrater reliability with Cohen κ statistics. We describe the counseling concepts present within patient-oncologist conversations and present illustrative quotes to describe how they were discussed. RESULTS: Oncologists generally provided patients who had yet to initiate therapy comprehensive medication information; those in the midst of treatment received less information. Oncologists discussed patients’ continued use of the medication (or discontinuation) among all patients who had initiated therapy (N = 18). How the patient was taking the medication (ie, therapy implementation) was less commonly discussed. Medication adverse effects were also discussed in all encounters. Self-management strategies were commonly provided, albeit mostly in response to a presenting symptom and not preemptively. Patients’ use of concurrent medications, financial access to therapy, and assessments of logistical arrangements were discussed more sporadically. CONCLUSION: Using audio recordings from a national sample of patient-oncologist office visits, we identified several potentially important opportunities to enhance medication counseling among patients prescribed capecitabine for the treatment of colorectal cancer.

Background Regorafenib is an oral multikinase inhibitor targeting angiogenesis, oncogenesis, and cancer proliferation/metastasis. This study evaluated the efficacy of regorafenib in refractory biliary tract cancer (BTC) in a multi-institutional phase 2 study. Methods Patients with BTC who progressed on at least 1 line of systemic therapy received regorafenib at 160 mg daily for 21 days on and 7 days off. The primary endpoint was 6-month overall survival (OS), and the secondary endpoints were median OS, progression-free survival (PFS), and objective response rates. Pretreatment plasma was collected for cytokine evaluation. Results A total of 39 patients were enrolled, and 33 were evaluable for efficacy. The median PFS and OS were 3.7 and 5.4 months, respectively, with survival rates of 46.2% at 6 months, 35.9% at 12 months, and 25.6% at 18 months for the intention-to-treat population. For the 33 evaluable patients who received regorafenib for at least 3 weeks, the median PFS and OS were 3.9 and 6.7 months, respectively, with survival rates of 51.5% at 6 months, 39.4% at 12 months, and 27.3% at 18 months. The objective response rate was 9.1%, and the disease control rate was 63.6%. Twenty-eight patients (71.8%) experienced grade 3/4 adverse events. Among the 23 cytokines analyzed, elevated baseline vascular endothelial growth factor D (VEGF-D) was associated with shorter PFS, whereas elevated baseline interleukin 6 (IL-6) and glycoprotein 130 (GP130) were associated with shorter OS. Conclusions Regorafenib demonstrated modest clinical efficacy in heavily pretreated patients with BTC. Further exploration of biomarkers is warranted to identify a group of patients with BTC who may benefit from regorafenib.

Background Preclinical evidence has demonstrated that common intratumor bacteria metabolize the chemotherapeutic drug gemcitabine. The significance of this bacterial metabolism pathway, relative to the known metabolic pathways by host enzymes, is not known. We hypothesized that bacterial metabolism is clinically significant and that “knockdown” by antibacterial therapy has the unintended effect of increasing the effective dose of gemcitabine, thereby increasing the risk for gemcitabine-associated toxicities. Materials and Methods We reanalyzed the comparator arm of the MPACT trial (NCT01442974), made available through Project Data Sphere, LLC (CEO Roundtable on Cancer's Life Sciences Consortium, Cary, NC; www.projectdatasphere.org). In this arm, 430 patients with metastatic pancreatic adenocarcinoma were treated with gemcitabine. We used the Anderson-Gill survival model to compare the risk of developing an adverse event after antibacterial prescription with time unexposed to antibacterials. Adverse events of grade 3 and greater were considered at three levels of granularity: all aggregated into one endpoint, aggregated by class, and taken individually. Antibiotic exposures were analyzed in aggregate as well as by class. Results Antibacterial exposure was associated with an increased risk of adverse events (hazard ratio [HR]: 1.77; confidence interval [CI]: 1.46–2.14), any hematologic adverse event (HR: 1.64; CI: 1.26–2.13), and any gastrointestinal adverse event (HR: 2.14; CI: 1.12–4.10) but not a constitutional (HR: 1.33; CI: 0.611–2.90) or hepatologic adverse event (HR: 0.99; CI: 0.363–2.71). Among specific adverse events, antibacterial exposure was associated with an increased risk of anemia (HR: 3.16; CI: 1.59–6.27), thrombocytopenia (HR: 2.52; CI: 1.31–4.85), leukopenia (HR: 3.91; CI: 1.46–10.5), and neutropenia (HR: 1.53; CI: 1.07–2.17) but not any other specific adverse events. Conclusion Antibacterial exposure was associated with an increased risk of gemcitabine-associated, dose-limiting adverse events, including aggregate hematologic and gastrointestinal events, as well as four specific hematologic adverse events, suggesting that intratumor bacteria may be responsible for a clinically significant portion of gemcitabine metabolism. Alternative avenues of evidence will be necessary to confirm this preliminary finding and assess its generalizability. There is plentiful opportunity for similar analyses on other clinical trial data sets, where gemcitabine or other biomimetic small molecules were used. Implications for Practice Patients treated with gemcitabine for metastatic pancreatic ductal adenocarcinoma have an increased rate of gemcitabine-associated toxicity during and after antibiotic therapy. This observation is consistent with preclinical evidence that intratumor bacteria metabolize gemcitabine to an inactive form. Further research is needed to determine whether this observation merits any changes in clinical practice.

Background: The pharmacy reference database, Micromedex, lists concomitant hydrochlorothiazide and cyclophosphamide use as a potential, major drug–drug interaction (DDI), although only one small, single-center study supports this claim. Our objective was to estimate associations between this potential DDI and two adverse chemotherapy-related events, neutropenia-related hospitalizations and treatment regimen discontinuation, among a cohort of women with breast cancer initiating adjuvant chemotherapy containing cyclophosphamide. Methods: Using linked Surveillance, Epidemiology, and End Results Program (SEER)-Medicare data, we included women 66 years and older with breast cancer diagnosis between 2007 and 2011, who initiated a regimen containing cyclophosphamide. Risk ratios (RR) and 95% confidence intervals for adverse outcomes comparing women exposed versus unexposed to the potential DDI were assessed using modified multivariable Poisson regression adjusting for potential confounders. Results: In total, 27% of women receiving cyclophosphamide treatment were exposed to concomitant hydrochlorothiazide, of which 11% experienced a neutropenia-related hospitalization and 21% discontinued their chemotherapy regimen prior to completion. Adjusted risks of both adverse events were similar between those exposed and unexposed to the potential DDI [neutropenia-related hospitalization: adjusted RR (aRR) = 0.92 (0.70–1.21); treatment discontinuation: aRR = 1.00 (0.96–1.05)]. Conclusions: Our results do not support an association between concomitant hydrochlorothiazide use and two clinically relevant adverse chemotherapy-related events. Impact: Our results support reassessing and potentially lowering severity of this potential interaction in drug reference databases.

No biomarkers are available to predict toxicities induced by VEGFR TKIs. This study aimed to identify markers of toxicities induced by these drugs using a discovery-validation approach. The discovery set included 140 sorafenib-treated cancer patients (TARGET study) genotyped for SNPs in 56 genes. The most significant SNPs associated with grade ≥2 hypertension, diarrhea, dermatologic toxicities, and composite toxicity (any one of the toxicities) were tested for association with grade ≥2 toxicity in a validation set of 201 sorafenib-treated patients (Alliance/CALGB 80802). The validated SNP was tested for association with grade ≥2 toxicity in 107 (LCCC 1029) and 82 (Italian cohort) regorafenib-treated patients. SNP-toxicity associations were evaluated using logistic regression, and a meta-analysis between the studies was performed by inverse variance. Variant rs4864950 in KDR increased the risk of grade ≥2 composite toxicity in TARGET, Alliance/CALGB 80802, and the Italian cohort (meta-analysis p=6.79×10(−4), OR=2.01, 95% CI 1.34–3.01). We identified a predictor of toxicities induced by VEGFR TKIs.

The American Cancer Society and American Institute for Cancer Research recommend that cancer survivors limit intake of red and processed meats. This recommendation is based on consistent associations between red and processed meat intake and cancer risk, particularly risk of colorectal cancer, but fewer data are available on red and processed meat intake after cancer diagnosis.To examine whether intake of unprocessed red meat or processed meat is associated with risk of cancer recurrence or mortality in patients with colon cancer.This prospective cohort study used data from participants with stage III colon cancer enrolled in the Cancer and Leukemia Group B (CALGB 89803/Alliance) trial between 1999 and 2001. The clinical database for this analysis was frozen on November 9, 2009; the current data analyses were finalized in December 2021.Quartiles of unprocessed red meat and processed meat intake assessed using a validated food frequency questionnaire during and 6 months after chemotherapy.Hazard ratios (HRs) and 95% CIs for risk of cancer recurrence or death and all-cause mortality.This study was conducted among 1011 patients with stage III colon cancer. The median (IQR) age at enrollment was 60 (51-69) years, 442 patients (44%) were women, and 899 patients (89%) were White. Over a median (IQR) follow-up period of 6.6 (1.9-7.5) years, we observed 305 deaths and 81 recurrences without death during follow-up (386 events combined). Intake of unprocessed red meat or processed meat after colon cancer diagnosis was not associated with risk of recurrence or mortality. The multivariable HRs comparing the highest vs lowest quartiles for cancer recurrence or death were 0.84 (95% CI, 0.58-1.23) for unprocessed red meat and 1.05 (95% CI, 0.75-1.47) for processed meat. For all-cause mortality, the corresponding HRs were 0.71 (95% CI, 0.47-1.07) for unprocessed red meat and 1.04 (95% CI, 0.72-1.51) for processed meat.In this cohort study, postdiagnosis intake of unprocessed red meat or processed meat was not associated with risk of recurrence or death among patients with stage III colon cancer.

Purpose Claudin-low molecular subtypes have been identified in breast and bladder cancers and are characterized by low expression of claudins, enrichment for epithelial-to-mesenchymal transition (EMT), and tumor-initiating cell (TIC) features. We evaluated whether the claudin-low subtype also exists in gastric cancer. Materials and Methods Four hundred fifteen tumors from The Cancer Genome Atlas (TCGA) gastric cancer mRNA data set were clustered on the claudin, EMT, and TIC gene sets to identify claudin-low tumors. We derived a 24-gene predictor that classifies gastric cancer into claudin-low and non–claudin-low subtypes. This predictor was validated with the Asian Cancer Research Group (ACRG) data set. We characterized molecular and clinical features of claudin-low tumors. Results We identified 46 tumors that had consensus enrichment for claudin-low features in TCGA data set. Claudin-low tumors were most commonly diffuse histologic type (82%) and originally classified as TCGA genomically stable (GS) subtype (78%). Compared with GS subtype, claudin-low subtype had significant activation in Rho family of GTPases signaling, which appears to play a key role in its EMT and TIC properties. In the ACRG data set, 28 of 300 samples were classified as claudin-low tumors by the 24-gene predictor and were phenotypically similar to the initially derived claudin-low tumors. Clinically, claudin-low subtype had the worst overall survival. Of note, the hazard ratios that compared claudin-low versus GS subtype were 2.10 (95% CI, 1.07 to 4.11) in TCGA and 2.32 (95% CI, 1.18 to 4.55) in the ACRG cohorts, with adjustment for age and pathologic stage. Conclusion We identified a gastric claudin-low subtype that carries a poor prognosis likely related to therapeutic resistance as a result of its EMT and TIC phenotypes.

Curcumin inhibits UDP-glucuronyltransferases, a primary metabolic pathway for cancer chemotherapeutic agents like irinotecan. Concurrent administration of both agents may exacerbate irinotecan toxicity. We conducted this phase I study to determine the safety of concurrent curcumin and irinotecan administration. Ten participants with advanced solid tumors received one of four doses (1, 2, 3, and 4 g) of a curcumin phosphatidylcholine complex (PC) orally daily, and 200 mg/m

BACKGROUND: Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair–deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair–deficient, locally advanced rectal cancer. METHODS: We initiated a prospective phase 2 study in which single-agent dostarlimab, an anti–PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair–deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy. RESULTS: A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, (18)F-fluorodeoxyglucose–positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported. CONCLUSIONS: Mismatch repair–deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; Clinical-Trials.gov number, NCT04165772.)

CRLX101 is a nanoparticle-drug conjugate with a camptothecin payload. We assessed the toxicity and pathologic complete response (pCR) rate of CRLX101 with standard neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer. A single-arm study was conducted with a 3 + 3 dose escalation phase Ib followed by phase II at the maximum tolerated dose (MTD). Thirty-two patients were enrolled with 29 (91%) patients having T3/4 and 26 (81%) N1/2 disease. In phase Ib, no patient experienced a dose limiting toxicity (DLT) with every other week dosing, while 1/9 patients experienced a DLT with weekly dosing. The weekly MTD was identified as 15 mg/m2. The most common grade 3-4 toxicity was lymphopenia, with only 1 grade 4 event. pCR was achieved in 6/32 (19%) patients overall and 2/6 (33%) patients at the weekly MTD. CRLX101 at 15 mg/m2 weekly with neoadjuvant CRT is a feasible combination strategy with an excellent toxicity profile. Clinicaltrials.gov registration NCT02010567.

PURPOSE CALGB/SWOG 80405 was a randomized phase III trial that found no statistically significant difference in overall survival (OS) in patients with first-line metastatic colorectal cancer treated with chemotherapy plus either bevacizumab or cetuximab. Primary tumor DNA from 843 patients has been used to discover genetic markers of OS. PATIENTS AND METHODS Gene mutations were determined by polymerase chain reaction. Microsatellite status was determined by genotyping of microsatellites. Tumor mutational burden (TMB) was determined by next-generation sequencing. Cox proportional hazard models were used, with adjusting factors. Interaction of molecular alterations with either the bevacizumab or the cetuximab arms was tested. RESULTS Patients with high TMB in their tumors had longer OS than did patients with low TMB (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.95]; P = .02). In patients with microsatellite instability–high (MSI-H) tumors, longer OS was observed in the bevacizumab arm than in the cetuximab arm (HR, 0.13 [95% CI, 0.06 to 0.30]; interaction P < .001 for interaction between microsatellite status and the two arms). Patients with BRAF mutant tumors had shorter OS than did patients with wild-type (WT) tumors (HR, 2.01 [95% CI, 1.49 to 2.71]; P < .001). Patients with extended RAS mutant tumors had shorter OS than did patients with WT tumors (HR, 1.52 [95% CI, 1.26 to 1.84]; P < .001). Patients with triple-negative tumors (WT for NRAS/ KRAS/ BRAF) had a median OS of 35.9 months (95% CI, 33.0 to 38.8 months) versus 22.2 months (95% CI, 19.6 to 24.4 months ) in patients with at least one mutated gene in their tumors ( P < .001). CONCLUSION In patients with metastatic colorectal cancer treated in first line, low TMB, and BRAF and RAS mutations are negative prognostic factors. Patients with MSI-H tumors benefited more from bevacizumab than from cetuximab, and studies to confirm this effect of MSI-H are warranted.

PURPOSE: The association between geriatric assessment (GA)–identified impairments and long-term health care use in older cancer survivors remains unknown. Our objective was to evaluate whether a GA performed at cancer diagnosis was predictive of hospitalizations and long-term care (LTC) use in older adult cancer survivors. METHODS: Older adults with GA performed between 3 months before through 6 months after diagnosis were included (N = 125). Patients with Medicare Parts A and B coverage and no managed care were identified. Hospitalizations and LTC use (skilled nursing or assisted living) were assessed up to 5 years postdiagnosis. GA risk measures were evaluated in separate Poisson models estimating the relative risk (RR) for hospital and LTC visits, adjusting for age and Charlson comorbidity score. RESULTS: The mean age of patients was 74 years, and the majority were female (80%) and white (90%). Breast cancer (64%) and early-stage disease (stages 0 to III, 77%) were common. Prefrail/frail status (RR, 2.5; P < .001), instrumental activities of daily living impairment (RR, 5.47; P < .001), and limitations in climbing stairs (RR, 2.94; P < .001) were associated with increased hospitalizations. Prefrail/frail status (RR, 1.86; P < .007), instrumental activities of daily living impairment (RR, 4.58; P < .001), presence of falls (RR, 6.73; P < .001), prolonged Timed Up and Go (RR, 5.45; P < .001), and limitations in climbing stairs (RR, 1.89; P < .005) were associated with LTC use. CONCLUSION: GA-identified impairments were associated with increased hospitalizations and LTC use among older adults with cancer. GA-focused interventions should be targeted toward high-risk patients to reduce long-term adverse health care use in this vulnerable population.

Cancers of unknown primary (CUPs) are histologically confirmed, metastatic malignancies with a primary tumor site that is unidentifiable on the basis of standard evaluation and imaging studies. CUP comprises 2-5% of all diagnosed cancers worldwide and is characterized by early and aggressive metastasis. Current standard evaluation of CUP requires histopathologic evaluation and identification of favorable risk subtypes that can be more definitively treated or have superior outcomes. Current standard treatment of the unfavorable risk subtype requires assessment of prognosis and consideration of empiric chemotherapy. The use of molecular tissue of origin tests to identify the likely primary tumor site has been extensively studied, and here we review the rationale and the evidence for and against the use of such tests in the assessment of CUPs. The expanding use of next generation sequencing in advanced cancers offers the potential to identify a subgroup of patients who have actionable genomic aberrations and may allow for further personalization of therapy.

International audience; Fluoropyrimidines (fluorouracil, capecitabine, and other analogs) are highly used anticancer drugs worldwide. However, patients with cancer treated with these drugs might experience severe, life-threatening toxicity because of germline genetic variation in the DPYD gene. This is a genetic predisposition with an established mechanistic basis that links genetic variation in the DPYD gene to an increase in systemic drug exposure, resulting in an increased risk of toxicity. Pharmacology guidelines provide recommendations on avoiding treatment with fluoropyrimidines or reducing their dose in patients carrying DPYD genetic variants conferring an increased risk of toxicity. However, oncology societies in the United States do not recommend systematic testing. Instead, on April 30, 2020, the European Society for Medical Oncology issued a document recommending genetic testing. In this scenario of contradicting information, practicing oncologists struggle with reaching an informed decision on whether genetic testing should be applied before treatment. This is mostly due to uncertainty about the clinical relevance of genetic testing from the perspective of a practicing oncologist. To reach an informed decision, practicing oncologists need access to concise information on the genetic variants to be tested and a practitioner-friendly interpretation of the test results. We believe this information is currently lacking. To our knowledge, for the first time, we provide a single guide for health care professionals to make an evidence-based decision about DPYD testing for patients with cancer. This article provides the essential knowledge base for oncologists to have an informed discussion with their patients about the genetic testing for DPYD. This document assists practitioners in quickly evaluating whether, when, where, and how to order a DPYD genetic test.

Lymph node metastases from hepatocellular carcinoma (HCC) represents a challenging clinical scenario with a poor prognosis, especially in the setting of prior liver transplant. Long-term survival is achievable in select patients with isolated lymph node metastases who undergo surgical resection, but little data exist regarding non-surgical options. For intrahepatic HCC, stereotactic body radiation therapy (SBRT) has emerged as a standard and effective nonsurgical treatment option. Here, we present three patients (two with prior liver transplant) with isolated lymph node metastases treated with curative intent using SBRT to doses of 30-45 Gy in three to five fractions. Two patients (with follow-up of 27 and 31 months) had a complete or near-complete response and remain cancer-free. One patient had intrahepatic HCC recurrence shortly after SBRT but stable disease in the treated lymph node metastasis at 20 months. Liver function remained excellent after radiation in all three patients, but one patient developed a grade 3 duodenal ulcer at 20 months that resolved with medical management. These cases illustrate the potential utility of SBRT as a non-invasive, definitive treatment option for patients with isolated lymph node metastases from HCC.

RESEARCH OBJECTIVE: Racial disparities in health care experiences and access are well‐documented. Yet, little is known regarding racial variations in the confluence of multiple health care access (HCA) experiences among cancer patients. We identified cancer patient subgroups with similar, co‐occurring HCA experiences, and evaluated racial differences in HCA subgroup membership. STUDY DESIGN: We used data from the University of North Carolina Health Registry/Cancer Survivorship Cohort. Participants completed a baseline questionnaire assessing demographics, health history, health‐related quality of life, and health care experiences. HCA was assessed along five domains (ie, doctor interpersonal manner, doctor communication, financial burden, time spent with doctor, and accessibility/convenience) using the RAND Patient Satisfaction Questionnaire. We used latent profile analysis to identify subgroups of patients with similar HCA experiences. Modified Poisson regressions were estimated to assess racial differences in HCA subgroup membership, adjusting for patient clinical and demographic characteristics. POPULATION STUDIED: Black and white breast, gastrointestinal, genitourinary, and head/neck cancer patients aged 18 or older and enrolled in the University of North Carolina Health Registry/Cancer Survivorship Cohort during 2010 to 2016. PRINCIPAL FINDINGS: Our analysis included 393 black (14.8%) and 2265 white (85.2%) participants. The latent profile analysis resulted in an optimal solution of 5 HCA profiles/subgroups, ranging from Low HCA to High HCA. Members of profile 1 (6.0% of sample) reported “Low” HCA along all HCA domains. Profile 2 (10.8%) consisted of individuals reporting low scores on every HCA domain except “financial burden,” where scores were moderate. Profile 3 (49.9%) members exhibited moderate scores on each HCA domain, while members of profile 4 (11.7%%) reported moderate HCA scores on most HCA domains, with the exception of low scores on “financial burden.” Profile 5 (21.7%) was comprised of patients reporting “High” HCA along every HCA domain. In unadjusted chi‐square comparisons, black patients were more likely to be in the “Low” HCA group (Profile 1) than whites (11.11% vs 5.3%, P

Background Regorafenib, a multikinase inhibitor that inhibits angiogenesis, growth, and proliferation, prolongs survival as monotherapy in patients with refractory colorectal cancer. This international, double-blind, placebo-controlled, multicenter trial assessed the efficacy of regorafenib with folinic acid, fluorouracil, and irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer. Methods Patients with metastatic colorectal cancer who progressed on first-line oxaliplatin and fluoropyrimidine enrolled at 45 sites in the United States and Ireland. Patients, stratified by prior bevacizumab use, were randomized 2:1 to regorafenib or placebo. The treatment consisted of FOLFIRI on days 1 and 2 and days 15 and 16 with 160 mg of regorafenib or placebo on days 4 to 10 and days 18 to 24 of every 28-day cycle. Crossover was not allowed. The primary endpoint was progression-free survival (PFS). Under the assumption of a 75% event rate, 180 patients were required for 135 events to achieve 90% power to detect a hazard ratio (HR) of 0.65 with a 1-sided α value of .1. Results One hundred eighty-one patients were randomized (120 to regorafenib-FOLFIRI and 61 to placebo-FOLFIRI) with a median age of 62 years. Among these, 117 (65%) received prior bevacizumab or aflibercept. PFS was longer with regorafenib-FOLFIRI than placebo-FOLFIRI (median, 6.1 vs 5.3 months; HR, 0.73; 95% confidence interval [CI], 0.53-1.01; log-rank P = .056). The median overall survival was not longer (HR, 1.01; 95% CI, 0.71-1.44). The response rate was higher with regorafenib-FOLFIRI (34%; 95% CI, 25%-44%) than placebo-FOLFIRI (21%; 95% CI, 11%-33%; P = .07). Grade 3/4 adverse events with a >5% absolute increase from regorafenib included diarrhea, neutropenia, febrile neutropenia, hypophosphatemia, and hypertension. Conclusions The addition of regorafenib to FOLFIRI as second-line therapy for metastatic colorectal cancer only modestly prolonged PFS over FOLFIRI alone. Cancer 2018. © 2018 American Cancer Society.

Objective Computerized tomography (CT) imaging is routine in oncologic care and can be used to measure muscle quantity and composition that may improve prognostic assessment of older patients. This study examines the association of single-slice CT-assessed muscle measurements with a frailty index in older adults with cancer. Materials and Methods Using the Carolina Senior Registry, we identified patients with CT imaging within 60days ± of geriatric assessment (GA). A 36-item Carolina Frailty Index was calculated. Cross-sectional skeletal muscle area (SMA) and Skeletal Muscle Density (SMD) were analyzed from CT scan L3 lumbar segments. SMA and patient height (m 2 ) were used to calculate skeletal muscle index (SMI). Skeletal Muscle Gauge (SMG) was calculated by multiplying SMI×SMD. Results Of the 162 patients, mean age 73, 53% were robust, 27% pre-frail, and 21% frail. Significant differences were found between robust and frail patients for SMD (29.4 vs 24.1 HU, p p =0.003), but not SMI (41.9 vs 39.5cm 2 /m 2 , p =0.29). After controlling for age and gender, for every 5 unit decrease in SMD, the prevalence ratio of frailty increased by 20% (PR=1.20 [1.09, 1.32]) while the prevalence of frailty did not differ based on SMI. Conclusions Muscle mass (measured as SMI) was poorly associated with a GA-based frailty index. Muscle density, which reflects muscle lipid content, was more associated with frailty. Although frailty and loss of muscle mass are both age-related conditions that are predictive of adverse outcomes, our results suggest they are separate entities.

The only US Food and Drug Administration (FDA)-approved first-line systemic therapy for hepatocellular carcinoma (HCC) is sorafenib; however, resistance or intolerance to sorafenib is unfortunately common. In this review, we briefly describe systemic therapies that can be considered for patients with HCC who show resistance or intolerance to sorafenib. For all patients with HCC who need systemic therapy, we strongly advocate for participation in clinical trials. Cytotoxic chemotherapy plays a minor role in the treatment of advanced HCC, with some data supporting the use of FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) and GEMOX (gemcitabine-oxaliplatin). Multi-target kinase inhibitors such as lenvantinib and regorafenib have recently met their primary endpoints as first- and second-line therapy, respectively, with regorafenib now representing the only FDA-approved drug for second-line treatment of HCC. Other targeted therapies remain under investigation, but results so far have not significantly changed clinical practice. Immunotherapy is an interesting area of research in the treatment of HCC with preclinical and early clinical data demonstrating exciting results; thus numerous investigational studies are currently focusing on immunotherapy in the treatment of HCC. While systemic treatment options in HCC remain a challenge for providers, in this review, we summarize the current literature and highlight areas of progress with respect to the treatment of patients with HCC and resistance or intolerance to sorafenib.

Introduction: Hepatocellular carcinoma (HCC) is a poor-prognosis cancer with a high symptom burden. Multidisciplinary HCC care is complex and unique in cancer medicine. We sought to determine whether the distinct process affects hospice use and how hospice affects end-of-life acute care utilization. Patients and Methods: Patients dying after HCC diagnosed from 2004 to 2011 were identified within SEER-Medicare. Hospice use and associated factors were described using logistic regression. Coarse exact and propensity score matching created groups of hospice and nonhospice comparators balanced on clinical characteristics. Health care use from first hospice claim to death and the matched duration in the nonhospice group were compared. Results: Of 7,992 decedent patients with HCC, 63% used hospice before death, with a median duration of 18 days (interquartile range, 5-51 days). Initial treatment with surgery and ablation (odds ratio [OR], 0.63; 95% CI, 0.53 to 0.74) or chemoembolization/radioembolization (OR, 0.71; 95% CI, 0.62 to 0.80) was associated with decreased odds of subsequent hospice use compared with untreated patients. Hospice use was more likely in those consulting hematology/oncology (OR, 1.33; 95% CI, 1.13 to 1.56) but not in those consulting gastroenterology (OR, 0.79; 95% CI, 0.65 to 0.95). Hospice patients had lower rates of hospitalization (7.9% v 47.8%; risk ratio [RR], 0.16; 95% CI, 0.14 to 0.19), intensive care unit stay (2.8% v 25.3%; RR, 0.11; 95% CI, 0.09 to 0.14), and in-hospital death (3.5% v 58.4%; RR, 0.06; 95% CI, 0.05 to 0.07). Conclusion: Processes of care influence which patients with HCC are referred to hospice. Hospice use has a marked effect on acute care use at the end of life in patients with HCC. Efforts to incorporate cancer-focused palliative care might improve the quality of end-of-life care in HCC.

Background Academic physicians, such as those affiliated with National Cancer Institute (NCI)–designated Comprehensive Cancer Centers, may have different practice patterns regarding the use of high-cost cancer drugs than nonacademic physicians. Materials and Methods For this cohort study, we linked cancer registry, administrative, and demographic data for patients with newly diagnosed cancer in North Carolina from 2004 to 2011. We selected cancer types with multiple U.S. Food and Drug Administration–approved, National Comprehensive Cancer Network–recommended treatment options and large differences in reimbursement between higher-priced and lower-priced options (stage IV colorectal, stage IV lung, and stage II–IV head-and-neck cancers). We assessed whether provider's practice setting—NCI-designated Comprehensive Cancer Center (“NCI”) versus other location (“non-NCI”)—was associated with use of higher-cost treatment options. We used inverse probability of exposure weighting to control for patient characteristics. Results Of 800 eligible patients, 79.6% were treated in non-NCI settings. Patients treated in non-NCI settings were more likely to receive high-cost treatment than patients treated in NCI settings (36.0% vs. 23.2%), with an unadjusted prevalence difference of 12.7% (95% confidence interval [CI], 5.1%–20.0%). After controlling for potential confounding factors, non-NCI patients remained more likely to receive high-cost treatment, although the strength of association was attenuated (adjusted prevalence difference, 9.6%; 95% CI −0.1%–18.7%). Exploratory analyses suggested potential heterogeneity across cancer type and insurance status. Conclusion Use of higher-cost cancer treatments may be more common in non-NCI than NCI settings. This may reflect differential implementation of clinical evidence, local practice variation, or possibly a response to the reimbursement incentives presented by chemotherapy billing.

Background Multiple claims-based proxy measures of poor function have been developed to address confounding in observational studies of drug effects in older adults. We evaluated agreement between these measures and their associations with treatment receipt and mortality in a cohort of older colon cancer patients. Methods Medicare beneficiaries age 66+ diagnosed with stage II-III colon cancer were identified in the Surveillance, Epidemiology, and End Results-Medicare database (2004-2011). Poor function was operationalized by: (1) summing the total poor function indicators for each model; and (2) estimating predicted probabilities of poor function at diagnosis. Agreement was evaluated using Fleiss' κ and Spearman's correlation. Associations between proxy measures and: (1) laparoscopic versus open surgery; (2) chemotherapy versus none; (3) 5-fluorouracil (5FU)+oxaliplatin (FOLFOX) versus 5FU monotherapy; and (4) 1-year mortality were estimated using log-binomial regression, controlling for age, sex, stage, and comorbidity. Survival estimates were stratified by functional group, age, and comorbidity. Results Among 29,687 eligible colon cancer patients, 67% were 75+ years and 45% had stage III disease. Concordance across the poor function indicator counts was moderate (κ: 0.64) and correlation of predicted probability measures varied (ρ: 0.21-0.74). Worse function was associated with lower chemotherapy and FOLFOX receipt, and higher 1-year mortality. Within age and comorbidity strata, poor function remained associated with mortality. Conclusions While agreement varied across the claims-based proxy measures, each demonstrated anticipated associations with treatment receipt and mortality independent of comorbidity. Claims-based comparative effectiveness studies in older populations should consider applying one of these models to improve confounding control.

Upfront chemoradiation with omission of surgery (CR-only) is increasingly being used to treat rectal cancer. When CR-only is used with curative intent, intense surveillance is recommended. We hypothesized that in practice, few patients treated with CR-only receive intensive post-treatment surveillance.Using Surveillance, Epidemiology, and End Results (SEER)-Medicare, all nonmetastatic rectal cancer patients (≥66 years old) diagnosed from 2004 to 2012, who received upfront chemoradiation, were included. Patients who received CR-only were compared with patients receiving neoadjuvant therapy plus proctectomy. In the 24 months after treatment, markers of surveillance, including carcinoembryonic antigen testing (CEA), endoscopy, and imaging, were compared between groups.A total of 2,482 individuals met the inclusion criteria: 21% (n = 514) had CR-only and 79% had conventional treatment (ie chemoradiation plus proctectomy). Only 2.5% and 3.4% of those in the CR-only and conventional treatment groups, respectively, were in complete compliance with National Comprehensive Cancer Network surveillance guidelines during the first 2 years post-treatment (p0.01). The CR-only group was less likely than the conventional treatment group to receive: CEA (adjusted risk ratio [aRR] 0.57; 95% CI 0.50 to 0.65), endoscopy (aRR 0.76; 95% CI 0.66 to 0.87), and office visits (aRR 0.88; 95% CI 0.84 to 0.92), respectively. However, there were similar rates of cross-sectional imaging between groups (aRR 1.31; 95% CI 0.93 to 1.85).Adherence to guideline-recommended surveillance was poor for all Medicare patients with rectal cancer. Despite recommendations for closer follow-up, patients treated with CR-only were less likely to receive surveillance than those treated with conventional treatment. Efforts should be made to increase adherence to surveillance guidelines for all rectal cancer patients treated with curative intent, but particularly for those with higher risk of recurrence, such as those treated with CR-only.